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THE ROLE OF MONOAMINE OXIDASE IN BEHAVIORAL PLASTICITY
by
Sean C. Godar
_______________________________________________________
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
December 2010
Copyright 2010 Sean C. Godar

Monoamine oxidase (MAO) is the primary catabolic enzyme for the oxidative deamination of monoamines and has been implicated in several neuropsychiatric disorders. Cogent evidence has documented that both the MAO A and MAO B isoenzymes play a role in emotional regulation, suggesting that the behavioral abnormalities associated with MAO deficiency are underpinned by alterations in emotional processing. Although it has been well-established that MAO A deficiency leads to aggression and antisocial personality, the neurobiological substrates underlying these behavioral disturbances are still unclear. Moreover, little is known about the contribution of the MAO B isoenzyme in modulating emotional behaviors. To this end, I hypothesized that MAO A and B function through the regulation of behavioral plasticity, defined as the ability to properly integrate the perceptual information and emotional processing with appropriate behavioral outcomes. In order to test this hypothesis, the present set of studies investigated the behavioral responses of MAO A-deficient mice to foreign elements and predator-related cues. These experiments were complemented by testing the changes in behavioral responses of MAO A-deficient mice following exposure to stress-inducing stimuli. Although MAO A-deficient mice exhibited aversive defensive responses to foreign inanimate objects, this was accompanied by a profound reduction in reactivity to both potential threat and stress-inducing stimuli. To examine the specific contribution of low MAO A activity on behavioral outcomes, I characterized a novel line of hypomorphic MAO A mutant mice. Specifically, the hypomorphic mutant mice were tested for anxiety-related manifestations, aggression, and perseverative behaviors. Hypomorphic MAO A mutant mice displayed an increase in compulsive and anxiety-related behaviors and context-dependent alterations in aggression.; Since clinical reports of MAO A deficiency document describe a constellation of behavioral abnormalities that are highly reminiscent to autistic spectrum disorders, I tested whether MAO A-deficient mice exhibited behavioral alterations relevant to autistic-related symptomatology. Genetic ablation of MAO A activity resulted in a spectrum of autistic-related manifestations, including antisocial behaviors, behavioral inflexibility, and disturbances in communication. In order to investigate the role of MAO B in emotional regulation, I designed a series of behavioral tasks aimed to capture different facets of behavioral disinhibition. Abrogation of MAO B activity in mice led to a marked reduction in anxiety-related parameters, as well as novelty-seeking and risk taking behaviors, signifying behavioral disinhibition. Finally, I examined the possibility that the MAO isoenzymes influence behavior through modulation of the NMDA glutamatergic receptor function by treating transgenic MAO mutant mice with sub-threshold doses of the NMDA receptor antagonist dizocilpine. NMDA receptor blockade resulted in profound stereotyped behaviors and severe impairments in locomotor coordination in MAO A-, but not MAO B-deficient mice. Taken together, these findings indicate that MAO A deficiency causes marked disturbances in NMDA receptor function that may contribute to the dramatic behavioral abnormalities in MAO A- and MAO A/B-deficient lines. The present set of findings show that MAO plays a critical role in the regulation of behavioral plasticity.

THE ROLE OF MONOAMINE OXIDASE IN BEHAVIORAL PLASTICITY
by
Sean C. Godar
_______________________________________________________
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
December 2010
Copyright 2010 Sean C. Godar